Introduction of a Phe377del Mutation in ANK Creates a Mouse Model for Craniometaphyseal Dysplasia

Authors

  • I-Ping Chen,

    1. Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA
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  • Chiachien J Wang,

    1. Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA
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  • Sara Strecker,

    1. Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA
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  • Boguslawa Koczon-Jaremko,

    1. Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA
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  • Adele Boskey,

    1. Hospital for Special Surgery, New York, New York, USA
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  • Ernst J Reichenberger

    Corresponding author
    1. Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA
    • Address correspondence to: Ernst Reichenberger, PhD, University of Connecticut Health Center (UCHC), Center for Restorative Medicine and Skeletal Development, Department of Reconstructive Sciences, 263 Farmington Avenue, Farmington, CT 06030-3705, USA
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  • The authors state that they have no conflicts of interest

  • Published online on February 16, 2009

Abstract

Craniometaphyseal dysplasia (CMD) is a monogenic human disorder characterized by thickening of craniofacial bones and flaring metaphyses of long bones. Mutations for autosomal dominant CMD have been identified in the progressive ankylosis gene ANKH. Previous studies of Ank loss-of-function models, Anknull/null and Ankank/ank mice, suggest that Ank plays a role in the regulation of bone mineralization. However, the mechanism for Ank mutations leading to CMD remains unknown. We generated the first knockin (KI) mouse model for CMD expressing a human mutation (Phe377 deletion) in ANK. Homozygous Ank knockin mice (AnkKI/KI) replicate many typical features of human CMD including hyperostosis of craniofacial bones, massive jawbones, decreased diameters of cranial foramina, obliteration of nasal sinuses, fusion of middle ear bones, and club-shaped femurs. In addition, AnkKI/KI mice have increased serum alkaline phosphatase and TRACP5b, as reported in CMD patients. Biochemical markers of bone formation and bone resorption, N-terminal propeptide of type I procollagen and type I collagen cross-linked C-terminal telopeptide, are significantly increased in AnkKI/KI mice, suggesting increased bone turnover. Interestingly, AnkKI/KI bone marrow–derived macrophage cultures show decreased osteoclastogenesis. Despite the hyperostotic phenotype, bone matrix in AnkKI/KI mice is hypomineralized and less mature, indicating that biomechanical properties of bones may be compromised by the Ank mutation. We believe this new mouse model will facilitate studies of skeletal abnormalities in CMD at cellular and molecular levels.

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